The kappa opioid agonist U50,488 potentiates 6-hydroxydopamine-induced neurotoxicity on dopaminergic neurons

Several observations support the hypothesis that kappa opioid (κ-opioid) receptor agonism may contribute to neurotoxicity, but other reports have suggested that certain κ-agonists can attenuate neurological dysfunction. Degeneration of dopaminergic neurons in the substantia nigra is the pathological hallmark of Parkinson's disease. Therefore, it is of particular interest to study whether κ-opioid receptor agonism has an influence on the progressive degeneration of dopaminergic neurons. We have investigated the effect exerted by the selective κ-agonist U50,488 on the neurotoxicity induced by intrastriatal 6-hydroxydopamine (6-OHDA) administration on dopaminergic neurons. Male Sprague-Dawley rats received an acute (0.5 mg/kg) or subacute (0.5 mg/kg, twice at day, for 7 days) administration of U50,488, receiving the last dose 30 min before intrastriatal 6-OHDA administration. Acute or subacute U50,488 pretreatment potentiated the 6-OHDA-induced decrease in the number of nigral tyrosine hydroxylase immunoreactive neurons (P < 0.05). Acute U50,488 pretreated animals showed a tendency, although not statistically significant to increase striatal mRNA encoding for enkephalin (PPE mRNA). Subacute U50,488 significantly potentiated the increase in PPE mRNA induced by 6-OHDA (P < 0.05). The present results show a neurotoxic effect of the kappa agonist U50,488 on dopaminergic neurons in rats with a striatal lesion induced by 6-OHDA. This neurotoxic effect is associated to an increase in striatal PPE mRNA levels, suggesting that an increase in the indirect pathway activity and consequently an increase in the activity of the subthalamo-nigral pathway might be involved in this phenomenon. © 2004 Elsevier Inc. All rights reserved.This research was supported by grants from the Ministerio de Sanidad y Consumo (FIS 01/1499) and from the Ministerio de Ciencia y Tecnología (SAF2000-0212) of Spanish Government. J.B. and J.S. were supported by a grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Peer Reviewe